Heat Shock Protein 90 Inhibitors Protect and Restore Pulmonary Endothelial Barrier Function

Antonov, Alexander S.; Snead, Connie; Gorshkov, Boris A; Antonova, Galina; Verin, Alexander D.; Catravas, John D.

doi:10.1165/rcmb.2007-0324oc

Cited by 67 publications

(75 citation statements)

References 53 publications

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“…Mice treated with 17-DMAG showed an increased expression of HSP70 and decreased expression of the inflammatory markers STAT3 and NFkB. Similar results were observed in an in vitro model using bovine pulmonary arterial endothelial cells (42) as well as in a murine model of lung injury and sepsis (43).…”

Section: Discussionsupporting

confidence: 78%

Genomic Profiles and Predictors of Early Allograft Dysfunction After Human Liver Transplantation

Kurian

Fouraschen

Langfelder

et al. 2015

American Journal of Transplantation

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y These authors contributed equally to this manuscript.Early hepatic allograft dysfunction (EAD) manifests posttransplantation with high serum transaminases, persistent cholestasis, and coagulopathy. The biological mechanisms are poorly understood. This study investigates the molecular mechanisms involved in EAD and defines a gene expression signature revealing different biological pathways in subjects with EAD from those without EAD, a potential first step in developing a molecular classifier as a potential clinical diagnostic. Global gene expression profiles of 30 liver transplant recipients of deceased donor grafts with EAD and 26 recipients without graft dysfunction were investigated using microarrays of liver biopsies performed at the end of cold storage and after graft reperfusion prior to closure. Results reveal a shift in inflammatory and metabolic responses between the two time points and differences between EAD and non-EAD. We identified relevant pathways (PPARa and NF-kB) and targets (such as CXCL1, IL1, TRAF6, TIPARP, and TNFRSF1B) associated with the phenotype of EAD. Preliminary proof of concept gene expression classifiers that distinguish EAD from non-EAD patients, with Area Under the Curve (AUC) >0.80 were also identified. This data may have mechanistic and diagnostic implications for EAD.

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Section: Discussionsupporting

confidence: 78%

Genomic Profiles and Predictors of Early Allograft Dysfunction After Human Liver Transplantation

Kurian

Fouraschen

Langfelder

et al. 2015

American Journal of Transplantation

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“…HDAC inhibitors abrogate deacetylation of Hsp90, resulting in the accumulation of acetylated Hsp90. Because we have previously shown that Hsp90 promotes EBD and ALI/ARDS (4,16,40), in this project we determined the role of HDAC in LPS-mediated EBD in cultured HLMVEC. We hypothesized and demonstrated that LPS-induced HDAC activity functions upstream of Hsp90, and inhibition of HDAC would suppress Hsp90 chap- erone function.…”

Section: Discussionmentioning

confidence: 99%

“…The ATP-dependent molecular chaperone heat shock protein 90 (Hsp90) plays a central role in LPS-mediated EBD (4,16).…”

mentioning

confidence: 99%

Histone deacetylase inhibitors prevent pulmonary endothelial hyperpermeability and acute lung injury by regulating heat shock protein 90 function

Joshi

Barabutis

Birmpas

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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In this study we assessed the role of HDAC in mediating lipopolysaccharide (LPS)-induced transendothelial hyperpermeability and acute lung injury (ALI). We demonstrate that HDAC inhibition protects against LPS-mediated EBD. Inhibition of multiple HDAC by the general inhibitors panobinostat or trichostatin provided protection against LPS-induced transendothelial hyperpermeability, acetylated and suppressed Hsp90 chaperone function, and attenuated RhoA activity and signaling crucial to endothelial barrier function. Treatment with the HDAC3-selective inhibitor RGFP-966 or the HDAC6-selective inhibitor tubastatin A provided partial protection against LPS-mediated transendothelial hyperpermeability. Similarly, knock down of HDAC3 and HDAC6 by specific small-interfering RNAs provided significant protection against LPS-induced EBD. Furthermore, combined pharmacological inhibition of both HDAC3 and -6 attenuated the inflammation, capillary permeability, and structural abnormalities associated with LPS-induced ALI in mice. Together these data indicate that HDAC mediate increased transendothelial hyperpermeability caused by LPS and that inhibition of HDAC protects against LPS-mediated EBD and ALI by suppressing Hsp90-dependent RhoA activity and signaling.

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“…We have previously shown that inhibition of Hsp90 protects and restores LPS-induced hyperpermeability in bovine pulmonary arterial endothelial cells (BPAECs) (5,20). However, the underlying mechanisms involved in this protection by Hsp90 inhibitors are yet to be determined.…”

Section: Clinical Relevancementioning

confidence: 99%

“…Western blot analyses and immunoprecipitation experiments were performed as described previously (5,20). Densitometry was performed using Imagequant 5.1 (GE Healthcare Bio-Sciences, Pittsburgh, PA) and plotted as fold change from vehicle.…”

Section: Western Blotting and Immunoprecipitationmentioning

confidence: 99%

Heat Shock Protein 90 Inhibitors Prevent LPS-Induced Endothelial Barrier Dysfunction by Disrupting RhoA Signaling

Joshi

Dimitropoulou

Thangjam

et al. 2014

Am J Respir Cell Mol Biol

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Permeability of the endothelial monolayer is increased when exposed to the bacterial endotoxin LPS. Our previous studies have shown that heat shock protein (Hsp) 90 inhibitors protect and restore LPS-mediated hyperpermeability in bovine pulmonary arterial endothelial cells. In this study, we assessed the effect of Hsp90 inhibition against LPS-mediated hyperpermeability in cultured human lung microvascular endothelial cells (HLMVECs) and delineated the underlying molecular mechanisms. We demonstrate that Hsp90 inhibition is critical in the early phase, to prevent LPS-mediated hyperpermeability, and also in the later phase, to restore LPS-mediated hyperpermeability in HLMVECs. Because RhoA is a well known mediator of endothelial hyperpermeability, we investigated the effect of Hsp90 inhibition on LPS-mediated RhoA signaling. RhoA nitration and activity were increased by LPS in HLMVECs and suppressed when pretreated with the Hsp90 inhibitor, 17-allylamino-17 demethoxy-geldanamycin (17-AAG). In addition, inhibition of Rho kinase, a downstream effector of RhoA, protected HLMVECs from LPS-mediated hyperpermeability and abolished LPS-induced myosin light chain (MLC) phosphorylation, a target of Rho kinase. In agreement with these findings, 17-AAG or dominant-negative RhoA attenuated LPSinduced MLC phosphorylation. MLC phosphorylation induced by constitutively active RhoA was also suppressed by 17-AAG, suggesting a role for Hsp90 downstream of RhoA. Inhibition of Src family kinases also suppressed RhoA activity and MLC phosphorylation. Together, these data indicate that Hsp90 inhibition prevents and repairs LPS-induced lung endothelial barrier dysfunction by suppressing Src-mediated RhoA activity and signaling.

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Heat Shock Protein 90 Inhibitors Protect and Restore Pulmonary Endothelial Barrier Function

Cited by 67 publications

References 53 publications

Genomic Profiles and Predictors of Early Allograft Dysfunction After Human Liver Transplantation

Genomic Profiles and Predictors of Early Allograft Dysfunction After Human Liver Transplantation

Histone deacetylase inhibitors prevent pulmonary endothelial hyperpermeability and acute lung injury by regulating heat shock protein 90 function

Heat Shock Protein 90 Inhibitors Prevent LPS-Induced Endothelial Barrier Dysfunction by Disrupting RhoA Signaling

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